Frank Dunn Kern was an American mycologist and phytopathologist. He was born in 1883, died in 1973, and spent much of his life studying and teaching botany at Penn State. His 37 years at Penn State are honored by the name of our graduate school building, the Kern Graduate School. Kern studied pathogenic rust fungus, a topic he referenced frequently in his talk for the Botanical Society of America’s symposium on “The Genetic Relationship of Organisms,” held on December 30, 1914.  I recently found a transcript of his talk, later published in the American Journal of Botany, and couldn’t help but wish that Kern was still alive to give another lecture at Penn State.

His 1914 talk, titled “The Genetic Relationship of Parasites,” posed questions in regard to rust fungi, which 100 years later I find incredibly relevant when posed in the context of malaria. The CIDD seminar series has a tradition of allowing students to interview and meet lecturers post-seminar, but as Kern and I missed each other somewhere in the too-large generation gap, I wanted to have an imaginary interview, pretending to have just attended what must have been a fascinating seminar, and am basing his responses on the content of his lecture transcript. Kern’s talk, given before the era of Watson and Crick and the DNA-based field of genetics, covered broad topics ranging from the evolution of parasites, the genetic relationships between hosts in multihost systems, the taxonomic classifications of hosts and parasites, the evolution of sexuality, generalist vs. specialist trade-offs and virulence theory. An ambitious set of topics for one lecture but Kern covered all of them effectively.  It should be noted that Kern did not study malaria, though I think good things would have happened if he had, and I am thus taking much creative license in hypothesizing what he would have said about the malaria system.

An up close photograph of rust fungus. Image courtesy of Wikimedia Commons.

Me: So Frank, I study malaria — how is rust fungus like malaria?

Frank Dunn Kern (FDK): Malaria and rust fungus are both heteroecious, meaning that they undergo both sexual and asexual phases of reproduction to complete their life cycles. Both separate the sexual and asexual life stages in different hosts, taking sexual forms in an intermediate host, and mostly asexual forms in the primary host. There is a tendency in rust fungi to have the “gametophytic hosts higher in classification than the telial hosts […].” Might there may be a similar trend in heteroecious protozoa, like malaria, in their asexual phase hosts vs. sexual phase hosts?

Me: We see that malaria vectors host the sexual phase of the parasites, while the vertebrate hosts harbor asexual phases. That is true for malaria across taxa and seems to be the case for trypanosomes and Leishmania major. I have no idea why this is the case. (If anyone knows I would love to have the theory explained to me).

FDK: In rust fungus, historic evidence from when the parasite was autoecious has indicated that evolution to heteroecious forms has resulted in the original autoecious host evolving to be the gametophytic host and the novel host taking on the role of the telial host. Understanding the evolution of malaria into its intermediate and primary hosts might help you in understanding whether there is a parallel in these systems.

To continue answering your question, there are other similarities as well. Both malaria and rust fungi are obligate parasites. Both are pleimorphic, showing very different phenotypes in different host environments. And, at a basic level of similarity, both are eukaryotes.

Me: Your lecture mentioned the use of parasites to better understand genetic relationships between host species, and thus to better organize taxonomic groups. If in 40 years we discover the nature of genetic material coding for differences between hosts, do you think we will see host-host relationships predicting genetic similarities more strongly than other factors such as morphologic similarities predicting genetic similarities? [Watson and Crick’s discovery of the double helix is not until 1953, 39 years after 1914]

FDK: When I started studying Gymnosporangium, I found that the fungus was not only found on hosts in the juniper and apple families, but also on a member of the rose family, and later on a member of the hydrangea family. Though these families were not always classified in the same order, further morphological studies reclassified them as such and my argument in favor of using parasites to show relatedness is favored by the reclassification grouping. In future research, when we can see the genetic material of these hosts and do a more precise comparison of similarity, I think we might find this trend in many types of hosts where the ability to share parasites might indicate shared genetic factors.

Me: We can ask that question better with an understanding of the genetic code. Humans are hypothesized to have acquired malaria from other apes, the same is true for SIV/HIV and Ebola. Is this a trend where humans are more likely to experience spillover from more closely related species? Do we acquire novel pathogens from other apes more frequently than from raccoons or bats or cats? It seems possible that we would be more likely to share similar pathogens with hosts similar in species to us. In the example of dogs acquiring parvovirus from cats with feline panleukemia virus, could that also be explained by genetically similar hosts more easily experiencing spillover than ones that are genetically very different? Were dogs any more likely than humans to get a feline virus or were they just victims of chance? If the genetic similarity theory has credence, than dogs were more likely because of their genetic relatedness to cats. It seems to me like humans are more likely to be infected by diseases of other mammals than by diseases of reptiles or amphibians, or plants.

FDK: That is something future research on genetics may be able to tell us. Hopefully we will get an answer.

[End of the interview].

Imaginary interviews are wonderful because I can end the conversation whenever I want, rather than waiting for the already-decided end time or for a socially appropriate point in conversation.  If you have never read Kerns work, I think it deserves reading by malariologists. Rust fungi and malaria have similar evolutionary history and I wonder how much of their evolution can be explained by the same story. Did malaria evolve from being autoecious in humans similar to the rust fungus in juniper? When malaria spills over into novel hosts can these host types be predicted by host genetics? Is there a pattern in which host environment asexual forms prefer and which host environment sexual forms prefer? And what explains this pattern?

I defended my thesis last week, which feels pretty much as Katey described it: a sudden, disorienting shift in momentum. During my time at Penn State, I learned that I really enjoy my work and I plan to continue in academia as long as that’s true. I also learned that models are most fun when they tell me things I didn’t expect, and fortunately that happens a lot. In that sense, the model described in this editorial by Jim Austin is one of the least-fun I’ve encountered. The statistical model has been developed into a Science widget that  is supposed to tabulate the likelihood that one will become a principal investigator. Unsurprisingly, Austin reports that the probability is always predicted to be higher for male scientists and that female scientists are predicted to need two extra first-author publications to make up for not being male. Identifying discrimination is useful, because it forces us to examine what we are doing to contribute to the problem. Case in point: this PNAS paper showing that faculty (male and female) consistently rank male students as more competent and hireable than female students with identical CVs. The model underlying the science widget serves the same function: highlighting the disparities that currently exist, so that they can be addressed. But I’m torn about whether the widget is useful, and in fact I’m worried that it could be worse than useless–do women need more reasons to give up on academia? Or is the widget just a more-accessible way of emphasizing an unacceptable bias?

For myself, the widget is worse than useless, and I’d rather not waste time wondering whether I belong in science when there’s science to be had. And if women’s contributions tend to be undervalued, I’ll mention two women who have contributed enormously to research across fields: Ada Lovelace, who wrote the first computer program, paving the way for science as we know it, and Grace Wahba, whose work on splines is frankly inspiring. And as a modest contribution of my own: animated splines!

Best transmission investment strategy and corresponding payoff.

As someone who studies infectious diseases, one thing that continues to amaze me about infectious diseases is how improbably their persistence can seem.

When I was in Tanzania, one of the technicians invited me to visit a local hospital with him. This particular hospital specializes in treating people with leprosy, which made me curious about how leprosy is transmitted. As it turns out, part of the answer seems to be pretty rarely. According to one paper, about 95% of people are resistant to infection by the mycobacterium that causes leprosy.*

A few days after visiting the leprosy hospital, I went to a meeting where a researcher mentioned in passing that the number of Anopheles mosquitoes, let alone malaria infected Anopheles mosquitoes, captured in Dar es Salaam seems extremely low and yet malaria persists at a relatively steady rate (something like 10%, if I remember correctly).

The other day, as I lay under a bednet in the insectary here at Penn State, it struck me as highly unlikely that such a frail little insect could find an unprotect human host even once in her lifespan, let alone twice. And not just any humans, but to feed on a malaria-infected human and survive long enough to transmit by feeding on another human. And yet, the WHO estimates over 200 million malaria cases in 2012, so it’s not as unlikely as it seems to me, watching the mosquitoes bounce off my net.

* As a side note, I once spent a month shadowing an infectious disease doctor at a hospital in the U.S. The doctor mostly treated people with bacterial infections secondary to other medical issues like diabetes or cancer. He also treated some HIV+ patients and occasionally, a patient with TB which, like leprosy, is caused by a mycobacterium. I realized I was probably better suited for research or public health when I was more interested in the when and why of the TB cases than the treatment plans the doctor devised for his patients.

As infectious disease biologists, our ears perk up at the mention of pathogens in a system and we begin to wonder if and how they might be important in shaping or driving patterns.

I often find myself pausing after anecdotal stories in books, articles, etc and wishing the authors would elaborate. Why is it Mr. Theodore Roosevelt that there are invisible lines that abruptly signal the presence or absence of ticks in the depths of the Amazon? Are you telling me Tim Cope, young adventurer extraordinaire, that Mongolia is one of the few places that people can commonly get plague?

I’ll elaborate on the second thought here. First off, let it be known that little research has been done on plague in Mongolia, and the bulk of the literature is in Chinese or Russian (thereby inaccessible to this writer). Instances of transmitted plague to humans have been actively recorded since 1897. The hosts for plague include a variety of mammals including species of marmots, pika, suslik (read ground squirrels) and voles, but the most important in transmitting to humans is the charismatic and delectable (according to Mongolians) marmot.

More interestingly, instances of plague have been recorded from the 1300s on the fringes of the Mongol empire. In a popularly cited account by the Italian Gabriele de’ Mussi, he describes the siege of Caffa (today, Feodosija in Crimea). This port city held a mix of Italian traders and their Mongol hosts who often bumped heads. An escalation of tensions in 1343 led to an attack led by the Mongol leader Janibeg that lasted until 1347 when the Italians were allowed to remain in Caffa. Interestingly, this incident is posed as one of the very first instances of biological warfare. In 1346, the combative Mongols were struck by a devastating disease that contributed to the decision to allow the Italians to remain at the port. Gabriele de’ Mussi describes the scene:

“The dying Tartars, stunned and stupefied by the immensity of the disaster brought about by the disease, and realizing that they had no hope of escape, lost interest in the siege. But they ordered corpses to be placed in catapults and lobbed into the city in the hope that the intolerable stench would kill everyone inside.”

In addition, it was thought for a time that contaminated Italians fleeing the scene contributed to the introduction of plague into Western Europe. New analysis reveals that this was probably not the case, however.

See where infectious disease rabbit holes can take you? From beautiful scenes on the steppe to rotten, diseased corpses and medieval catapults.

Sex ratios are really interesting, especially when they’re really skewed.
(This interest scientists, and also fans of science fiction – check out Y the Last Man where a virus kills all creatures on earth with an XY chromosome pairing).

Well, here’s an example of a skew in the opposite direction. Imagine you introduce a genotype into a population that produces 95% males because males are genetically engineered such that any X chromosome produced in sperm is shredded, resulting in only males in the next generation. This is happening in mosquito populations and is being touted as a means for controlling these pests in the linked news article. Useful for controlling the spread of pathogens that only females transmit with blood meals.

What worries me is that the release of male mosquitoes that produce mainly male mosquitoes is going to be a rapid-fire evolutionary dead end. There’s a huge fitness disadvantage to a male biased skew. Is this even worth doing? A waste of money? What are your thoughts or predictions about evolutionary outcomes?

I spent last week at the Ecology and Evolution of Infectious Diseases conference at Colorado State, which had a slew of excellent talks including an entire morning devoted to the topic of how to present science as an interesting narrative rather than a dry series of findings. Amidst the fascinating science, I learned a couple of shocking things about prions from Edward Hoover‘s talk. While we have yet to see a zombie disease transmitted through human populations, Hoover aptly describes prions as zombie proteins, which turn normal proteins into aberrant forms that aggregate into plaques in neural tissue and cause extensive damage, leading ultimately–and inevitably–to death.

Hoover presented evidence that diluting prions can prevent infection, or at least slow its progression. I wanted to know whether that’s because the animal immune system can cope with small numbers of prions, or whether prions themselves are less efficient when there are few of them. I hold out hope for some immunity against prions, but what I found was this nice article by Silveira and colleagues showing that prions need to aggregate together to zombify normal proteins (terminology mine) and make animals sick. Interestingly, there seems to be a maximum size for effective zombification of normal proteins, beyond which prions are less efficient. One of the hallmarks of prion diseases is plaques in the brain tissue, and research has focused on preventing those plaques from forming, but Silveira et al. suggest that actually concentrating prions into large plaques may be a good thing, slowing the progression of the disease.

Hoover and others also passaged prions through different animals to get prions that were better at infecting other species and with shorter incubation periods. Thus prions appear to be evolving by natural selection, but without any kind of genetic change. So prions can evolve, and quickly, while normal proteins are constrained to change at the sluggish pace set by mammalian generation times. Now instead of wondering why mammals haven’t evolved better defenses against prions, I wonder why we’re not all up to our ears in prions. Thoughts?